title: Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a major unsolved health problem. Most drugs that pass preclinical tests fail in these patients, emphasizing the need of improved preclinical models to test novel anticancer strategies. Here, we developed four orthotopic mouse models using primary human PDAC cells genetically engineered to express firefly- and Gaussia luciferase, simplifying the ability to monitor tumor growth and metastasis longitudinally in individual animals with MRI and high-frequency ultrasound. In these models, we conducted detailed histopathologic and immunohistochemical analyses on paraffin-embedded pancreatic tissues and metastatic lesions in liver, lungs, and lymph nodes. Genetic characteristics were compared with the originator tumor and primary tumor cells using array-based comparative genomic hybridization, using frozen specimens obtained by laser microdissection. Notably, the orthotopic human xenografts in these models recapitulated the phenotype of human PDACs, including hypovascular and hypoxic areas. Pursuing genomic and immunohistochemical evidence revealed an increased copy number and overexpression of c-Met in one of the models; we examined the preclinical efficacy of c-Met inhibitors in vitro and in vivo. In particular, we found that crizotinib decreased tumor dimension, prolonged survival, and increased blood and tissue concentrations of gemcitabine, synergizing with a cytidine deaminase-mediated mechanism of action. Together, these more readily imaged orthotopic PDAC models displayed genetic, histopathologic, and metastatic features similar to their human tumors of origin. Moreover, their use pointed to c-Met as a candidate therapeutic target in PDAC and highlighted crizotinib and gemcitabine as a synergistic combination of drugs warranting clinical evaluation for PDAC treatment.
authors.affiliation: Authors' Affiliations: Departments of Medical Oncology, Hematology, Neurosurgery and Pediatric Oncology/Hematology, Neuro-oncology Research Group, VU University Medical Center; Diagnostic Oncology Division, Netherlands Cancer Institute; VisualSonics, Amsterdam, the Netherlands; Departments of Neurology and Pediatrics, Stanford University School of Medicine, Stanford, California; Division of Surgical Pathology, Division of General and Transplant Surgery, University of Pisa, Pisa, Italy; and Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Amir
authors.initials: A
authors.lastname: Avan
authors.forename: Viola
authors.initials: V
authors.lastname: Caretti
authors.forename: Niccola
authors.initials: N
authors.lastname: Funel
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.forename: Mina
authors.initials: M
authors.lastname: Maftouh
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Honeywell
authors.forename: Tonny
authors.initials: T
authors.lastname: Lagerweij
authors.forename: Olaf
authors.initials: O
authors.lastname: Van Tellingen
authors.forename: Daniela
authors.initials: D
authors.lastname: Campani
authors.forename: Dieter
authors.initials: D
authors.lastname: Fuchs
authors.forename: Henk M
authors.initials: HM
authors.lastname: Verheul
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Schuurhuis
authors.forename: Ugo
authors.initials: U
authors.lastname: Boggi
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000077547:Crizotinib; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D003841:Deoxycytidine; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met; D000093542:Gemcitabine